Published on Monday, January 14, 2013,
updated Monday, January 14, 2013

Changing one letter in the genetic code at a precise location now possible

Scientists at the Massachusetts Institute of Technology and
Rockefeller and Harvard universities have found a new method of
editing DNA with great precision. This and another new technique
mean that scientists can now go into a cell, find a particular
sequence in the genome and change that sequence by a single
letter.

Just to get your mind around this feat, imagine taking about
5,000 different novels and reprinting them in normal font size on
23 very long cotton ribbons. Since each word takes up about half an
inch, the ribbons, placed end to end, would stretch for roughly
three million miles-120 times around the world. But to be a bit
more realistic, twist and tangle the ribbons so much that they only
go around the planet once.

One of the books written on your ribbons is "A Tale of Two
Cities," but you don't even know which ribbon it is on, let
alone where on that ribbon. Your task is to find the
clauses "It was the beast of times, it was the worst of times" and
correct the misprint.

Little wonder that precision genetic engineering has taken a
while to arrive. In truth, it has been moving steadily toward
greater precision for 10,000 years. Early farmers in what's now
Turkey introduced a mutation to wheat plants in the "Q
gene" on chromosome 5A, which made the seed-head less brittle and
the seed husks easier to harvest efficiently.

They did so unknowingly, of course, by selecting from among
random mutations.

Fifty years ago, scientists used a nuclear reactor to fire gamma rays at
barley seeds, scrambling some of their genes. The result was
"Golden Promise," a high-yielding, low-sodium barley variety
popular with (ironically) organic farmers and brewers. Again, the
gene editing was random, the selection afterward nonrandom.

Twenty years ago, scientists inserted specific sequences for four enzymes
into rice plants so that they would synthesize vitamin A and
relieve a deadly vitamin deficiency-the result being "golden rice."
This time the researchers knew exactly what letters they were
putting in but had no idea where they would end up.

In recent years, it has become possible to insert a DNA sequence
into a specific location on a chromosome using "zinc finger
proteins," which recognize target sequences. But these will work
only for certain sequences, and with low efficiency. More recently,
a process known by the acronym Talens has proved more
adaptable.

This week, Recombinetics of St. Paul, Minn., patented
gene-editing technologies that employ Talens for use in livestock
improvement. As a first application in agriculture, Recombinetics
has used Talens to introduce into Holstein dairy cattle the key
mutation (found naturally in Red Angus beef cattle) that keeps
horns from growing. The plan is to avoid having to physically
dehorn dairy calves, a stressful and expensive procedure.

Scott Fahrenkrug, chief executive of Recombinetics, points out
that you could crossbreed Holstein and Angus to achieve the same
result, but it would dilute the milk-producing traits in the
Holstein. The firm aims to produce pigs and cattle that are more
resistant to disease and to use the technology to correct
fertility-compromising mutations in cattle that have emerged in
selective-breeding programs.

The latest technique, from a team led by Feng
Zhang of MIT, promises to be even cheaper than Talens, but it is
still in the early stages of development. It hijacks a recently
discovered genetic trick that bacteria use to fight off viruses,
known by the acronym Crispr. One of the Crispr enzymes in
particular, Cas9, the scientists report, can be used for "precise
cleavage"-accurate DNA cutting-in human and mouse cells. Moreover,
both Talens and Crispr can be aimed at several sites
simultaneously-greatly accelerating the process of gene
editing.